Antibacterial agents
View Patent ↗Antibacterial compounds of formula I are provided: As well as stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.
1. A compound according to the formula IA:
or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
D is absent or selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
Y is selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted heterocyclyl; and
(3) substituted heteroaryl;
R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl;
A is selected from the group consisting of
(1) —C(R 1a , R 2a )OR 3a ; and
(2) —C(R 1a , R 2a )N(R 4a , R 5a );
wherein R 1a , R 2a , R 3a , R 4a , and R 5a are independently selected from the group consisting of
(1) H; and
(2) substituted and unsubstituted C 1 -C 6 -alkyl.
2. The compound of claim 1 , wherein A is —C(R 1a ,R 2a )OR 3a .
3. The compound of claim 2 , wherein A is —CH 2 OH.
4. The compound of claim 2 , wherein A is —CH(CH 3 )OH.
5. A compound according to the formula IB:
or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
D is absent or selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
G is —C≡C—C≡C—;
Y is selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl;
A is —C(R 1a ,R 2a )N(R 4a ,R 5a );
wherein R 1a , R 2a , R 4a , and R 5a are independently selected from the group consisting of
(1) H; and
(2) substituted and unsubstituted C 1 -C 6 -alkyl.
6. A compound according to Formula VIII:
or stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof, wherein
E is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C 1 -C 6 -alkyl,
(3) substituted or unsubstituted aryl,
(4) substituted or unsubstituted heterocyclyl, and
(5) substituted or unsubstituted heteroaryl,
or E and R 3L , together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring, having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S;
R 1L , R 3L are independently selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C 1 -C 6 -alkyl,
(3) C 1 -C 6 -alkyl substituted with aryl,
(4) C 1 -C 6 -alkyl substituted with heterocyclyl, and
(5) C 1 -C 6 -alkyl substituted with heteroaryl,
or R 1L and R 3L , together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring, having from 5 to 7 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
7. A compound of claim 5 according to Formula IX:
or stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof, wherein
E is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C 1 -C 6 -alkyl,
(3) substituted or unsubstituted aryl,
(4) substituted or unsubstituted heterocyclyl, and
(5) substituted or unsubstituted heteroaryl,
or E and R 3L , together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring, having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S;
R 1L , R 3L are independently selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C 1 -C 6 -alkyl,
(3) C 1 -C 6 -alkyl substituted with aryl,
(4) C 1 -C 6 -alkyl substituted with heterocyclyl, and
(5) C 1 -C 6 -alkyl substituted with heteroaryl,
or R 1L and R 3L , together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring, having from 5 to 7 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
8. A compound of claim 5 according to Formula X:
or stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof, wherein
E is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C 1 -C 6 -alkyl,
(3) substituted or unsubstituted aryl,
(4) substituted or unsubstituted heterocyclyl, and
(5) substituted or unsubstituted heteroaryl,
or E and R 3L , together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring, having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system are selected from N, O and S;
R 1L , R 3L are independently selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C 1 -C 6 -alkyl,
(3) C 1 -C 6 -alkyl substituted with aryl,
(4) C 1 -C 6 -alkyl substituted with heterocyclyl, and
(5) C 1 -C 6 -alkyl substituted with heteroaryl,
or R 1L and R 3L , together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring, having from 5 to 7 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system are selected from N, O and S.
9. A compound according to the formula IA:
or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
D is absent or selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
Y is selected from the group consisting of
(1) substituted or unsubstituted aryl;
(2) substituted or unsubstituted heterocyclyl; and
(3) substituted or unsubstituted heteroaryl;
R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl;
A is —C(R 1a ,R 2a )N(R 4a ,R 5a );
wherein R 1a , R 2a , R 4a , and R 5a are independently selected from the group consisting of
(1) H; and
(2) substituted and unsubstituted C 1 -C 6 -alkyl.
10. The compound of claim 9 , wherein A is —CH 2 NH 2 .
11. The compound of claim 9 , wherein A is —CH(CH 3 )NH 2 .
12. The compound of claim 9 , wherein D is absent and Y is a substituted or unsubstituted aryl.
13. The compound of claim 9 , wherein D is a substituted or unsubstituted aryl and Y is a substituted or unsubstituted aryl.
14. A compound according to the formula IA:
or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
D is absent or selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
Y is an unsubstituted aryl;
R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl; and
A is —CH 2 OH.
15. The compound of claim 14 , wherein D is absent.
16. The compound of claim 14 , wherein D is a substituted or unsubstituted aryl.
17. A compound according to the formula IA:
or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
D is absent or selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
Y is selected from the group consisting of
(1) substituted aryl; and
(2) substituted heterocyclyl; and
(3) substituted heteroaryl;
R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl; and
A is —CH(CH 3 )OH.
18. The compound of claim 17 , wherein D is absent and Y is a substituted aryl.
19. A compound according to the formula IA:
or a stereoisomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
D is selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
Y is selected from the group consisting of
(1) substituted or unsubstituted C 3 -C 8 -cycloalkyl;
(2) substituted or unsubstituted aryl;
(3) substituted or unsubstituted heterocyclyl; and
(4) substituted or unsubstituted heteroaryl;
R 4 is H or substituted or unsubstituted C 1 -C 6 -alkyl;
A is selected from the group consisting of
(1) —C(R 1a ,R 2a )OR 3a ; and
(2) —C(R 1a ,R 2a )N(R 4a ,R 5a );
wherein R 1a , R 2a , R 3a , R 4a , and R 5a are independently selected from the group consisting of
(1) H; and
(2) substituted and unsubstituted C 1 -C 6 -alkyl.
20. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
21. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable excipient.
22. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable excipient.
23. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable excipient.
24. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable excipient.
25. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable excipient.
26. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable excipient.
27. A pharmaceutical composition comprising a compound of claim 1 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
28. A pharmaceutical composition comprising a compound of claim 5 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
29. A pharmaceutical composition comprising a compound of claim 6 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
30. A pharmaceutical composition comprising a compound of claim 9 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
31. A pharmaceutical composition comprising a compound of claim 14 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
32. A pharmaceutical composition comprising a compound of claim 17 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
33. A pharmaceutical composition comprising a compound of claim 19 , a second agent, and a pharmaceutically acceptable excipient, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
34. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 1 .
35. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 5 .
36. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 6 .
37. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 9 .
38. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 14 .
39. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 17 .
40. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 19 .
41. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 1 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
42. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 5 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
43. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 6 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
44. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 9 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
45. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 14 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
46. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 17 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
47. A method of inhibiting LpxC comprising administering to a patient in need thereof, an effective amount of the compound of claim 19 and an effective amount of a second agent, wherein the second agent is an antibacterial agent, an antiendotoxin agent, or an inhaled non-antibacterial agent for the treatment of respiratory tract infection.
48. The compound of claim 19 , wherein D is a substituted or unsubstituted aryl and Y is a substituted or unsubstituted aryl.